Project 3: Autophagy dysfunction and neuronal activity in FTD Ana Maria Cuervo SUMMARY This proposal investigates the interplay between pathogenic forms of tau and selective forms of autophagy in the context of frontotemporal dementia (FTD). We will coordinate the activities of this project with those of Project 1 and Project 2 to test our working hypothesis that tau-mediated toxicity in the autophagic pathways underlie the basis for the altered tau proteostasis and functional alterations observed in FTD-affected neurons. Project 3 will use cutting edge proteomics (MS Core) and genetics (CRISPR Core) in iPSC-derived neurons to investigate: 1) effect of pathogenic intra- and extracellular tau in the activity of three different forms of selective autophagy; 2) consequences of blockage of each of these forms of autophagy on neuronal activity and tau uptake. Project 3 will also utilize postmortem frozen human brain tissue from controls and FTD-tau patients (Human Core) to identify 3) changes in the properties of tau associated with autophagic compartments in control and patient brains. Assisted by the CRISPR Core, we will modulate levels of differentially tau- interacting proteins and address the effect of this intervention on autophagy and neuronal activity. Integration of data (Data Core) generated by this project with that from the other two projects in the Center will allow us to elucidate the contribution of tau toxicity on the autophagic system to the neuronal activity imbalance observed in FTD.